1. Field of the Invention
This invention relates generally to methods of treating aggressive cancers, such as hormone-refractory metastatic prostate cancer, by exposing the aggressive cancer cells to curcumin analogs.
2. Description of the Related Prior Art
Prostate cancer has the highest incidence and the second highest cancer mortality in American men. The American Cancer Society estimates that 233,000 new cases of prostate cancer will be diagnosed and 29,480 men will die of prostate cancer in the United States in 2013 (American Cancer Society, 2014). Current therapies (radical prostatectomy, chemotherapy, local radiotherapy, or hormonotherapy) are successful in treating localized, androgen-dependent, prostate cancer. However, treatment of hormone-refractory prostate cancer remains hindered by inevitable progression of resistance to first-line treatment with docetaxel. Consequently, novel drugs are needed to treat advanced hormone-resistant prostate cancer (Feldman, et al., 2001; Corcoran, et al., 2012).
Curcumin or diferuloylmethane, a polyphenolic molecule extracted from the rhizome of the plant Curcuma longa (turmeric), is a yellow spice used as curry ingredient and has been used for centuries in Ayurvedic, Chinese, and Hindu medicine systems. There is a huge difference in the rate of incidence of prostate cancer between Western countries (120 prostate cancer incidents per 100,000 people in Northern America) and East Asian countries (less than 10 prostate cancer incidents per 100,000 people in Asia) (Lin, et al., 2005).
The increased risk of prostate cancer in the first generation of Asian men emigrating to the United States suggests a chemopreventive effect of Asian traditional food. Recent preclinical and clinical studies have demonstrated that curcumin has a number of anticancer properties (Aggarwal, et al., 2003; Chaturvedi, et al., 2011). The potential of curcumin to treat both androgen-dependent and androgen-independent prostate cancer has been demonstrated by the in vitro and in vivo studies (Aggarwal, 2008; Teiten, et al., 2010).
A new philosophy that favors multi-targeted drugs has recently gained momentum (Zimmerman, et al., 2007). Curcumin serves as a good example of a class of compounds that is able to target multiple enzymes with a “magic shotgun” (Brown, et al., 2013). The anticancer effects of curcumin are associated with its influence on numerous growth factors within the cell (Sharma, et al., 2004; Zhou, et al., 2011). The effect of curcumin on any particular growth factor is small, but its aggregate effect is significant. Curcumin's aggregate effects are especially valuable for diseases like cancer that are complex, inflammation associated, and often involve mutations in multiple genes. Because of its potential ability to treat hormone-refractory prostate cancer, its low molecular weight, lack of toxicity, and its mechanism of action against multiple targets, curcumin could be an ideal candidate as an androgen-independent agent against prostate cancer.
However, its clinical development has been limited by its suboptimal pharmacokinetics and poor bioavailability caused by poor solubility in water and rapid in vivo metabolism (Anand, et al., 2007). It has been found that, with oral administration at the dose of 450 mg-3600 mg/day in a phase I trial, the blood concentration of curcumin in plasma and target tissues falls under the detection limit (Garcea, et al., 2004). Curcumin has been used as a lead compound to design and synthesize analogs for the potential treatment of prostate cancer. Some analogs, such as JC-22 (Lee, 2010), FLLL11, and FLLL12 (Lin et al., 2009) were found to be more potent than curcumin towards PC-3 prostate cancer cell line.
Curcumin analogs also have promise as HIV and neurodegenerative treatment agents (US Pat. Pub No. 2014/0051742 A1) by showing anti-retroviral, neuroprotective, anti-glucosidase, and anti-HIV integrase properties. Curcumin analogs have shown anti-proliferative activity in tumor cells (US Pat. Pub No. 2012/0288555).
However, all of the curcumin analogs disclosed in the prior art have low bioavailability due to poor water solubility or suboptimal potency. There is the need to develop new and improved curcumin analogs with better potency, water solubility, and greater in vivo metabolic stability, as well as retained safety profiles.